Scope of Problem:
Chronic total occlusions (CTO) are an extremely common finding in patients undergoing diagnostic catheterization. Up to 20% of patients undergoing angiography have been reported to have one or more chronic total coronary occlusions1. Balloon angioplasty is one treatment modality for CTO with the first successful report appearing in 19822. Percutaneous coronary interventions (PCI) continue to increase annually with >1 million procedures world-wide in 19983, and CTO currently account for approximately 10%-15% of PCI4-7. However, since PCI have severe limitations in this patient subset, clinicians frequently decide to refer these patients for bypass surgery or persist with (often ineffective) medical therapy. The presence of one or more CTO of vessels supplying viable areas of myocardium remains one of the most common reasons for referral for bypass surgery rather than attempting PCI.
Limitations of PCI
The main limitations of PCI for CTO are the decreased procedural success rates compared to stenotic (but not totally occluded) arteries, and a high restenosis rate. The restenosis problems have improved with the use of coronary stents8-10. However, procedural success rates have only shown modest improvement in the past 20 years from 50-60% in the 1980's11,12 to 60-70% range in the 1990's5,13-15, due to some improvements in angioplasty equipment, such as hydrophilic guide wires16,17. In contrast, PCI enjoys success rates in excess of 95% in stenotic but non-occluded arteries. In fact, success rates of 70% is probably an overestimation of PCI success for CTO, since attempts are generally only made in lesions felt to have a reasonable chance of success. Several lesion characteristics have been identified that are predictors of procedural success and influence the decision to proceed with angioplasty. Duration of occlusion, which is often difficult to ascertain, is a major predictor. In instances where this can be reliably estimated, recent coronary occlusions (i.e. <3 months duration) have been reported in two studies to be successfully dilated in 74% and 89% of cases5,13. However, if the occlusion duration exceeds 3 months, success rates decline to 59% and 45%, respectively. Other variables that are predictive of procedural failure include long lesion length of the occluded segment (>15 mm)1,18,19, presence of bridging collaterals, absence of a tapered funnel leading into the occluded segment and possibly smaller vessel size20. Failure rates are also higher in absolute occlusions (no distal opacification) than in functional total occlusions (subtotal occlusion with faint late anterograde opacification of the distal segment without discernible continuity)6,19,21.
Why Do PCI Fail in Chronic Total Occlusions?
Inability to cross the CTO with a guide wire is the overwhelming reason for PCI failure, accounting for >75% of failures5,19. Recent technical innovations with newer types of guide wires designed specifically for total occlusions such as the Magnum™ wire22, the low speed rotational angioplasty device23,24 and excimer laser powered guide wire (Prima™ Total Occlusion Device)25-27 have not improved success rates compared to conventional guide-wire techniques28,29. Thus a purely mechanical approach of designing stiffer and more powerful guide wires to try and push through fibrotic total occlusions has only limited efficacy. Although thrombolytic therapy is effective in acute coronary occlusions, only a small number of native artery chronic occlusions have been treated with prolonged thrombolytic infusions with limited results30,31, and this strategy has largely been abandoned. There are no other published reports of pharmacologic treatments of chronically occluded arteries in order to improve angioplasty results.
Why Should CTO be Opened?
The myocardial territory supplied by a chronically occluded artery may still be viable, particularly in the situation of a slowly developing occlusion that is associated with extensive collateralization. Myocardial ischemia is a common sequelae of CTO since the blood flow through collaterals is inadequate in situations of increased myocardial demand (exercise, post-prandial, stress). Consequently, significant angina pectoris represents the most common cause of attempted PCI in the setting of CTO. The situation of inadequate blood supply to viable myocardium (termed “hibernating myocardium”) is also a major cause of potentially reversible myocardial dysfunction leading to heart failure. Moreover, there is accumulating data that CTO portend a poorer prognosis. A higher 2-year adjusted mortality rate has been reported in patients with a total occlusion compared with patients with subtotal occlusions32. In patients with single-vessel disease followed for a mean of 4 years, a significantly higher rate of sudden death (15%) occurred in patients with CTO than in patients with high grade stenosis (3%)33. Recent data has shown that revascularization of CTO improves left ventricular function (the main determinant of heart failure) and possible long-term mortality34-38. Suero and colleagues demonstrated a significant increase in 10-year survival for successful CTO treatment compared with failed CTO treatment (73.5% vs 65.1%)7. The survival benefit of an open artery may be due to enhanced electrical stability of the myocardium with reduction of ventricular tachyarrhythmias, absence of late potentials and the preservation of vagal tone53-55.
Experimental Use of Matrix Metalloproteinases:
Collagenase formulations have been used in in-vitro cell culture studies for a long period of time. These formulations act to isolate cells from tissue by degrading the surrounding matrix and these cells are then used for cell culture. There are very few reports of using collagenase formulations for in-vivo studies. An experimental model of intracerebral hemorrhage in rats has been developed by systemically infusing bacterial collagenase (type XI and type VII) or a combination of collagenase and heparin directly into the caudate nucleus48-50. In this model, erythrocytes accumulate around large caudate blood vessels 10 minutes after injection with extensive bleeding present at 4 hours, presumably due to degrading interstitial and basement membrane collagen in the thin-walled intracerebral vessels49.
Kerényi and colleagues51 have previously reported on using several different enzymes including collagenase in a rabbit atherosclerotic model. These enzymes were delivered through a double balloon catheter in which two balloons are inflated and the enzyme is injected into the space between the two inflated balloons. These enzymes were left for a maximum of 30 minutes and then the arteries were immediately removed. In this model, rabbits were fed a high cholesterol diet, which resulted in the development of modest atherosclerotic plaques that were minimally stenotic (approximately 30%) and therefore not occlusive or a barrier to passing a guidewire or angioplasty balloon catheter. Release of various enzymes (trysin or papain alone or in combination with collagenase) frequently resulted in not only dissolution of the plaques but also caused extensive damage to the media of the artery. Collagenase by itself had little effect. These studies support the rationale for using collagenase to degrade extracellular matrix within the vessel wall but also caution about the potential limitations of such a therapy with high doses, particularly in thin-walled arteries.
Thus, although there is some experimental basis to support the use of the matrix degradative properties of collagenase for atherosclerotic plaques in general, chronic total arterial occlusions are a unique manifestation of the atherosclerotic disease. Moreover, none of these studies address the unique clinical situation of a chronically occluded artery in which a long segment of artery is completely occluded and will not permit the passage of guide wires which are an absolute requirement for performing balloon angioplasty and stenting. In addition, the parameters of a successful therapeutic approach in this specific setting (chronic total occlusions) such as the exact enzyme composition and amount, local delivery strategy and appropriate incubation period of the enzymes prior to attempting guidewire crossing are unknown.
Experimental studies of chronically occluded arteries have been limited by the lack of a suitable animal model. Hyo-Chun Yoon et. al published a disclosure of a porcine animal model of a chronic peripheral arterial occlusion in the Journal of Interventional Radiology, January-February 1996 at pages 65-74. The model presented one month old and three month old occlusions. There was significant variation in the degree of organization within the occlusions. Infusion therapy with collagenase and urokinase were attempted, but patentcy was not restored in any animal and attempts at the passage of a guide wire through the occlusion were unsuccessful. Collagenase used after urokinase thereapy was indescriminate in its digestion of the native vessel and the organized thrombus. Yoon et al. summarized in their results that neither urokinase nor collagenase proved effective against chronic clot in the doses and time course studied with their porcine model.
Several issued patents have included some claims for the use of collagenase or other matrix degrading enzymes to reduce the amount of atherosclerotic plaque in a blood vessel. In U.S. Pat. No. 6,025,477, Calendoff teaches a method of directing enzymes to the atherosclerotic plaque through binding a proenzyme(s) [fibroblastic collagenase, gelatinase, polymorphonuclear collagenase, granulocytic collagenase, stromelysin I, stromelysin II or elastase] to a reagent (preferably a bifunctional antibody) that binds specifically to the atherosclerotic plaque to form a reagent-plaque complex (column 16; lines 61-66). The proenzyme, which is also bound to the reagent would then be activated by cleavage and be converted into an enzyme capable of dissolving a component of the plaque (column 42, lines 19-32).
In U.S. Pat. No. 5,811,248 (Ditlow) and U.S. Pat. No. 6,020,181 (Bini), similar methods of targeting delivery of matrix degrading enzymes to atherosclerotic plaques have been taught. Ditlow teaches a method of using a reagent comprising CDR-grafted antibody or fragment conjugated to an enzyme capable of digesting atherosclerotic plaque (column 5, lines 11-15). Bini teaches a method of binding fibrinolytic matrix metalloproteinases to moieties having specificity for a biological target molecule such as an antibody that would be preferentially directed to a fibrin(ogen) substrate for improving fibrin(ogen)olytic efficacy (column 14, lines 1-10). However, these methods of enzyme delivery would likely only be relevant for non-occluded arteries, particularly for generalized atherosclerosis disease. These teachings would not be applicable to the specific setting of performing angioplasty in occluded arteries, which receive very little circulating blood flow due to the complete occlusion. In this setting, much higher concentrations of enzymes are required which can only be achieved through a localized delivery system. Moreover, the exact parameters of the delivery and amounts of these enzymes must be optimized to ensure adequate alteration of the composition and substance of the occlusive plaque without damaging the outer layers (media and adventitia) of the arterial wall. In U.S. Pat. No. 6,020,181, Bini teaches a method of causing the degradation of fibrin (ogen) by means of fibrinolytic matrix metalloproteinases, preferably MMP-3 or MMP-7. This patent is relevant to acute arterial occlusions, which contain abundant thrombus and fibrin and are responsible for acute myocardial infarctions and sudden death. The method can be performed in vivo as a method of thrombolytic therapy in which a fibrinolytic matrix metalloproteinase is administered to a subject to degrade thrombus in situ. However, this application of the fibronolytic matrix metalloproteinase is not relevant to the problem of performing angioplasty in chronically occluded arteries, which contain extensive collagen and other extracellular matrix components and very minor amounts of fibrin or fibrinogen. In addition, as stated above, the systemic delivery method is not relevant to local delivery into arterial occlusions.
In summary, CTO remain an important subset of PCI lesions with quite limited success, predominantly due to inability of crossing the occlusion with a guide wire. The fibrotic, collagen-rich characteristic of these plaques is the underlying impediment to passing a guide wire. The vast majority of patients with symptomatic chronic total occlusions are either treated by medical therapy with often limited effectiveness or undergo invasive bypass surgery. In addition to causing significant angina, there is strong evidence that CTO are also associated with poorer left ventricular function and possibly worse survival than stenotic (but not occluded) lesions or successfully dilated chronic occlusions. Stenting of CTO has significantly improved long-term patency, which was the other limitation of angioplasty. Thus, the current evidence suggests that opening total occlusions by percutaneous interventions is underutilized and necessitates new approaches.
There is a need for a method of treatment of the plaque to facilitate guidewire passage through the occlusion as a prerequisite for successful angioplasty. More particularly, there is a need to chemically alter the collagen content and structure in these occlusive fibrous plaques to facilitate crossing with conventional guide wires.
There is a further need for an animal model of chronic total arterial occlusion to facilitate research and development methods treating chronic arterial occlusions which cannot be crossed by a conventional angioplasty guide wire.